There is a growing demand for highly concentrated low volume formulations of antibody therapies for subcutaneous administration, especially in the field of chronic disease therapy, to improve patient convenience and compliance by offering outpatient treatment.
For antibody drug substance manufacturing, ultrafiltration/diafiltration (UF/DF) is typically the final process step. Ultrafiltration is a membrane-based separation process that separates molecules in solution on the basis of size. Diafiltration is a specific type of ultrafiltration in which an aqueous buffer is added to the retentate. In this step, purified drug substance is concentrated and exchanged to protein concentration and excipient composition necessary for drug product formulation.
The predominant technology used in the industry for ultrafiltration/diafiltration (UF/DF) process is a form of tangential flow filtration (TFF) (see generally, Shiloach J. et al., 1988, Van Reis R. et al., 2001). In this technology, protein solution is recirculated under pressure, tangentially to an ultrafiltration membrane. This TFF approach works well for drug substance at low to moderate concentrations and in most cases a UF/DF process for one antibody is highly adaptable to another antibody with minimal changes. However, in situations with high protein concentrations, has come a series of technical challenges in process performance (see generally, Shire S J. et al., 2004, Luo R. et al., 2006, Shire S J., 2009).
The attainment of high concentration formulations by TFF technology can be difficult because highly concentrated protein solutions may lead to limited mass transfer due to decreased flux and eventual membrane fouling (see for example, Suki A. et al., 1984, 1986, Kim K J. et al., 1992). While that can be overcome by increasing the membrane surface area or replacing the membrane, it can lead to a lower yield. Another limitation is high viscosity may lead to high feed pressure, exceeding upper limit for membrane integrity during the process (see for example, Turker M. et al., 1987, Liu J. et al., 2005). While an implementation of an appropriate formulation design such as increase of ionic strength or addition of particular compounds can help decrease viscosity (see for example, Liu J. et al., 2006), it may be a challenging exercise to decrease the viscosity while ensuring the stable formulation composition. In situation where greater decreases in viscosity are required, it can be addressed by processing at elevated temperatures (see for example, Winter C., 2009). However, in such cases, protein stability may be compromised by prolonged exposure to higher temperatures. The problem to be solved by the present invention is therefore to provide a novel processing method to achieve high protein concentration by manipulating other processing parameters.